Hepatocyte growth factor (HGF), also known as scatter factor (SF), is a growth factor which is involved in various physiological processes, such as wound healing and angiogenesis. The high affinity interaction of HGF interaction with its receptor (c-Met) is implicated in tumour growth, invasion and metastasis.
Knudsen et al have reviewed the role of HGF and c-Met in prostate cancer, with possible implications for imaging and therapy [Adv. Cancer Res., 91, 31-67 (2004)]. Labelled anti-met antibodies for diagnosis and therapy are described in WO 03/057155.
c-Met has been shown to be involved in tumour growth, invasion and metastasis in many human cancers of epithelial origin. c-Met is expressed by most carcinomas and its elevated expression relative to normal tissue has been detected in cancers of: lung, breast, colorectal, pancreatic, head and neck, gastric, hepatocellular, ovarian, renal, glioma, melanoma and a number of sarcomas. In colorectal carcinoma (CRC), over-expression of c-Met has been detected in dysplastic aberrant crypt foci, the earliest pre-neoplastic lesions of the disease. In head and neck squamous cell cancer, c-Met is reportedly expressed or overexpressed in roughly 80% of primary tumours. In prostate cancer metastasis to bone, c-Met was reported overexpressed in over 80% of bone metastasis.
Under normal conditions, c-Met is expressed on epithelial cells and activated in a paracrine fashion, by mesenchymally derived HGF. The activation of c-Met in normal cells is a transient event and is tightly regulated. In tumour cells, however, c-Met can be constitutively active. In cancer, aberrant c-Met stimulation can be achieved through c-Met amplification/over-expression, activating c-Met mutations (e.g. structural alterations) and acquisition of autonomous growth control through creation of autocrine signalling loops. In addition, a defective down-regulation of the c-Met receptor will also contribute to aberrant c-Met expression in the cell membrane. While the over-expression of c-Met is HGF dependent (autocrine/paracrine), structural alterations caused by mutations are HGF independent (e.g. loss of extracellular domain).
WO 2004/078778 discloses polypeptides or multimeric peptide constructs which bind c-Met or a complex comprising c-Met and HGF. Approximately 10 different structural classes of peptide are described. WO 2004/078778 discloses that the peptides can be labelled with a detectable label for in vitro and in vivo applications, or with a drug for therapeutic applications. The detectable label can be: an enzyme, a fluorescent compound, an optical dye, a paramagnetic metal ion, an ultrasound contrast agent or a radionuclide. Preferred labels of WO 2004/078778 are stated to be radioactive or paramagnetic, and most preferably comprise a metal which is chelated by a metal chelator. WO 2004/078778 states that the radionuclides therein can be selected from: 18F, 124I, 125I, 131I, 123I, 77Br, 76Br, 99mTc, 51Cr, 67Ga, 47Sc, 167Tm, 141Ce, 111In, 168Yb, 175Yb, 140La, 90Y, 88Y, 153Sm, 166Ho, 165Dy, 166Dy, 62Cu, 64Cu, 67Cu, 97Ru, 103Ru, 186Re, 203Pb, 211Bi, 212Bi, 213Bi, 214Bi, 105Rb, 109Pd, 117mSu, 149Pm, 161Tb, 177Lu, 198Au and 199Au. WO 2004/078778 states (page 62) that the preferred radionuclides for diagnostic purposes are: 64Cu, 67Ga, 68Ga, 99mTc and 111In, with 99mTc being particularly preferred.
WO 2008/139207 discloses c-Met binding cyclic peptides of 17 to 30 amino acids which are labelled with an optical reporter imaging moiety suitable for imaging the mammalian body in vivo using light of green to near-infrared wavelength 600-1200 nm. The c-Met binding peptides comprise the amino acid sequence SEQ ID NO: 1:
Cysa-X1-Cysc-X2-Gly-Pro-Pro-X3-Phe-Glu-Cysd-Trp-Cysb-Tyr-X4-X5-X6;                wherein X1 is Asn, H is or Tyr;                    X2 is Gly, Ser, Thr or Asn;            X3 is Thr or Arg;            X4 is Ala, Asp, Glu, Gly or Ser;            X5 is Ser or Thr;            X6 is Asp or Glu;and Cysa-d are each cysteine residues such that residues a and b as well as c and d are cyclised to form two separate disulfide bonds. The optical reporter of WO 2008/139207 is preferably a cyanine dye.                        
WO 2009/016180 discloses c-Met binding cyclic peptides analogous to those of WO 2008/139207, wherein the optical reporter is a benzopyrylium dye. The agents of WO 2008/139207 and WO 2009/016180 are stated to be useful for in vitro and in vivo optical applications, especially optical imaging in vivo of the human body. Optical imaging of colorectal cancer is a preferred application.